RESUMEN
We present a natural history of a 32-year-old man with Hajdu-Cheney syndrome (HJCYS), because of the de novo truncating mutation in the exon 34 of NOTCH2 (c.6424-6427delTCTG, p.Ser2142ArgfsX4), who has been followed up for a period of 23 years (between 9 and 32 years). During follow-up, we observed abnormalities of vision, hearing, voice, and progression of craniofacial features in the form of skeletal dysplasia with affected skull, dentition, spine, limbs, fingers, and toes. Low bone mineral density and history of fragility fractures also suggested primary osteoporosis being a clinical manifestation. According to Stengel-Rutkowski, Schimanek, and Wernheimer (1984; Human Genetics, 6, 272-295), systematic data acquisition has been used for quantitative analysis of anthropological, radiographic, and clinical features at childhood, adolescence, and young adulthood separately. A detailed phenotype description together with the results of reanalysis of 14 reports so far published on patients with HJCYS and NOTCH2 mutation showed similar phenotype evolution with age. The spectrum of observed features may improve diagnostic tools for HJCYS at different periods of the lifespan.
Asunto(s)
Síndrome de Hajdu-Cheney/genética , Mutación/genética , Receptor Notch2/genética , Adolescente , Adulto , Secuencia de Bases , Niño , Análisis Mutacional de ADN , Progresión de la Enfermedad , Estudios de Seguimiento , Síndrome de Hajdu-Cheney/diagnóstico por imagen , Humanos , Masculino , Fenotipo , Adulto JovenRESUMEN
Brachydactyly refers to shortening of digits due to hypoplasia or aplasia of bones forming the hands and/or feet. Isolated brachydactyly type E (BDE), which is characterized by shortened metacarpals and/or metatarsals, results in a small proportion of patients from HOXD13 or PTHLH mutations, although in the majority of cases molecular lesion remains unknown. BDE, like other brachydactylies, shows clinical heterogeneity with highly variable intrafamilial and interindividual expressivity. In this study, we investigated two Polish cases (one familial and one sporadic) presenting with BDE and additional symptoms due to novel PTHLH mutations. Apart from BDE, the affected family showed short stature, mild craniofacial dysmorphism and delayed bone age. Sanger sequencing of PTHLH revealed a novel heterozygous frameshift mutation c.258delC(p.N87Tfs*18) in two affected individuals and one relative manifesting mild brachydactyly. The sporadic patient, in addition to BDE, presented with craniofacial dysmorphism, normal stature and bone age, and was demonstrated to carry a de novo heterozygous c.166C>T(p.R56*) mutation. Our paper reports on the two novel truncating PTHLH variants, resulting in variable combination of BDE and other symptoms. Data shown here expand the knowledge on the phenotypic presentation of PTHLH mutations, highlighting significant clinical variability and incomplete penetrance of the PTHLH-related symptoms.
Asunto(s)
Braquidactilia/genética , Anomalías Craneofaciales/genética , Enanismo/genética , Heterocigoto , Mutación , Proteína Relacionada con la Hormona Paratiroidea/genética , Fenotipo , Adolescente , Huesos/diagnóstico por imagen , Huesos/patología , Braquidactilia/diagnóstico , Niño , Preescolar , Anomalías Craneofaciales/diagnóstico , Análisis Mutacional de ADN , Enanismo/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , SíndromeRESUMEN
Desbuquois dysplasia type 2 (DBQD2) is a rare recessively inherited skeletal genetic disorder characterized by severe prenatal and postnatal growth retardation, generalized joint laxity with dislocation of large joints and facial dysmorphism. The condition was recently described to result from autosomal recessive mutations in XYLT1, encoding the enzyme xylosyltransferase-1. In this paper, we report on a Polish patient with DBQD2 who presented with severe short stature of prenatal onset, joint laxity, psychomotor retardation and multiple radiological abnormalities including short metacarpals, advanced bone age and exaggerated trochanters. Endocrinological examinations revealed that sleep-induced growth hormone (GH) release and GH peak in clonidine- and glucagon-induced provocative tests as well as insulin-like growth factor 1 (IGF-1) and IGF-binding protein-3 levels were all markedly decreased, confirming deficiency of GH secretion. Bone age, unlikely to GH deficiency, was significantly advanced. To establish the diagnosis at a molecular level, we performed whole-exome sequencing and bioinformatic analysis in the index patient, which revealed compound heterozygous XYLT1 mutations: c.595C>T(p.Gln199*) and c.1651C>T(p.Arg551Cys), both of which are novel. Sanger sequencing showed that the former mutation was inherited from the healthy mother, whereas the latter one most probably occurred de novo. Our study describes the first case of DBQD2 resulting from compound heterozygous XYLT1 mutation, expands the mutational spectrum of the disease and provides evidence that the severe growth retardation and microsomia observed in DBQD2 patients may result not only from the skeletal dysplasia itself but also from GH and IGF-1 deficiency.
Asunto(s)
Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/genética , Enanismo Hipofisario/diagnóstico , Enanismo Hipofisario/genética , Enanismo/diagnóstico , Enanismo/genética , Heterocigoto , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genética , Mutación , Osificación Heterotópica/diagnóstico , Osificación Heterotópica/genética , Pentosiltransferasa/genética , Fenotipo , Polidactilia/diagnóstico , Polidactilia/genética , Adulto , Análisis Mutacional de ADN , Exoma , Femenino , Haplotipos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Repeticiones de Microsatélite , Polonia , Embarazo , Diagnóstico Prenatal , Esqueleto/diagnóstico por imagen , Esqueleto/patología , UDP Xilosa Proteína XilosiltransferasaRESUMEN
BACKGROUND: Lehmann et al., [2003, 2006] have documented two different substitutions at position 486 of the BMPR1B gene which resulted in a phenotype of brachydactyly A2 [MIM 112600] or brachydactyly C with symphalangism [MIM 113100]. METHODS: In this article we report a family of Polish extraction with a novel mutation: c.1457G>T (R486L) which segregated with a complex brachydactyly. Clinical and radiological data are presented and details of previously reported patients with a pathogenic change of an amino acid at position 486 of the BMPR1B gene are summarized. CONCLUSION: Our data extends the previously known mutational and radiological spectrum associated with mutations in the BMPR1B gene and confirms the existence of a universal hotspot in the BMPR1B gene in this distinctive autosomal dominant brachydactyly disorder. It is of interest that an affected female in the Polish family had a severe congenital malformation of the venous system in addition to her digital anomalies. This observation raises the possibility of disturbance of embryonic angiogenesis by specific mutations in BMPR1B.
Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Braquidactilia/diagnóstico por imagen , Braquidactilia/genética , Mutación Missense/genética , Fenotipo , Venas/anomalías , Secuencia de Bases , Cartilla de ADN/genética , Femenino , Humanos , Datos de Secuencia Molecular , Polonia , Reacción en Cadena de la Polimerasa , Radiografía , Análisis de Secuencia de ADNRESUMEN
We document three new patients with fibular agenesis, tibial campomelia, and oligosyndactyly (FATCO). Two of these individuals had tetramelic manifestations while the third had bilateral abnormalities of the lower limbs. These patients and others reported as FATCO seem to belong to the phenotype "fibular aplasia with ectrodactyly." Genetic screening for CNVs and mutations in the TP63 and WNT10B genes did not show any genetic abnormalities. ©
Asunto(s)
Anomalías Múltiples/diagnóstico , Peroné/anomalías , Deformidades Congénitas de la Mano/diagnóstico , Anomalías Múltiples/genética , Niño , Femenino , Dedos/anomalías , Humanos , Recién Nacido , Deformidades Congénitas de las Extremidades , Masculino , Fenotipo , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Proteínas Wnt/genéticaRESUMEN
Sclerosteosis and Van Buchem disease are related recessive sclerosing bone dysplasias caused by alterations in the SOST gene. We tested the hypothesis that craniodiaphyseal dysplasia (CDD) (MIM 122860), an extremely rare sclerosing bone dysplasia resulting facial distortion referred to as "leontiasis ossea", could also be caused by SOST mutations. We discovered mutations c.61G>A (Val21Met) and c.61G>T (Val21Leu) two children with CDD. As these mutations are located in the secretion signal of the SOST gene, we tested their effect on secretion by transfecting the mutant constructs into 293E cells. Intriguingly, these mutations greatly reduced the secretion of SOST. We conclude that CDD, the most severe form of sclerotic bone disease, is part of a spectrum of disease caused by mutations in SOST. Unlike the other SOST-related conditions, sclerosteosis and Van Buchem disease that are inherited as recessive traits seem to be caused by a dominant negative mechanism.
Asunto(s)
Proteínas Morfogenéticas Óseas/genética , Marcadores Genéticos/genética , Dominios y Motivos de Interacción de Proteínas/genética , Señales de Clasificación de Proteína/genética , Anomalías Múltiples/genética , Proteínas Adaptadoras Transductoras de Señales , Niño , Anomalías Craneofaciales/genética , Femenino , Humanos , Masculino , Mutación , OsteocondrodisplasiasRESUMEN
Two stillborn male sibling fetuses born to the same parents had severe mesomelic dysplasia documented at ultrasound and confirmed by radiography and autopsy. The 17-week-old fetus with increased neck translucency had additional heart and great vessel anomalies consistent with tetralogy of Fallot. The 15-week-old fetus had a nuchal cystic hygroma. We posit that these sibs have a distinct, previously unreported skeletal dysplasia. The mode of genetic transmission could be autosomal recessive or X-linked recessive.
Asunto(s)
Feto/anomalías , Linfangioma Quístico/diagnóstico por imagen , Cuello/anomalías , Cuello/diagnóstico por imagen , Tetralogía de Fallot/complicaciones , Tetralogía de Fallot/diagnóstico por imagen , Ultrasonografía Prenatal , Adulto , Femenino , Feto/diagnóstico por imagen , Humanos , Linfangioma Quístico/complicaciones , Masculino , Medida de Translucencia Nucal , Embarazo , RadiografíaRESUMEN
DTDST mutations cause a spectrum of diastrophic dysplasia disorders characterized by defects of proteoglycans sulfation. Reduction of sulfate/chloride antiporter activity is manifested by lower sulfate uptake and depends on a combination of mutations in DTDST. We analyzed a family with an autosomal recessive form of bone dysplasia. Three affected brothers from this family are compound heterozygotes for C653S/A715V mutations. We classified their phenotype as a new intermediate form between diastrophic dysplasia and multiple epiphyseal dysplasia, manifested by shortening of stature, metatarsus adductus/club foot, mild brachydactyly, proximally placed thumbs and clinodactyly of the fifth fingers. Radiographs document platyspondyly most marked in the lower thoracic and upper lumbar spine, epiphyseal dysplasia affecting predominantly the femoral heads, widening of the metaphyses, narrow growth cartilage and multilayered patellae. Exaggerated lesser trochanters of femur, that is, "monkey wrench" sign, elevated greater trochanters, thin upper pubic rami, grossly normal carpal/tarsal bones and severe, early onset osteoarthritis were other notable features.
Asunto(s)
Proteínas de Transporte de Anión/genética , Mutación , Osteocondrodisplasias/genética , Fenotipo , Adulto , Transporte Biológico/genética , Enfermedades del Desarrollo Óseo/diagnóstico por imagen , Enfermedades del Desarrollo Óseo/genética , Genes Recesivos , Heterocigoto , Humanos , Masculino , Núcleo Familiar , Osteocondrodisplasias/diagnóstico por imagen , Proteoglicanos/genética , Radiografía , Transportadores de Sulfato , Sulfatos/metabolismoRESUMEN
A 6-year-old girl is described with a unique, rare type of tibial hemimelia known as Carraro syndrome (OIMI 275230). There are only two previous reports of this condition in the literature. In our patient, the tibia anomaly was associated with other skeletal abnormalities, hemivertebra and tetralogy of Fallot. This association of malformations has not previously been reported. We conclude that this girl has either a variant of Carraro syndrome or a new syndrome.
Asunto(s)
Ectromelia/clasificación , Niño , Ectromelia/diagnóstico por imagen , Femenino , Humanos , Radiografía , Columna Vertebral/anomalías , Síndrome , Tetralogía de Fallot/complicaciones , Tibia/anomalíasRESUMEN
BACKGROUND: The first case of Osteogenesis Imperfecta Type V in the Polish literature is reported. CASE REPORT: Skeletal survey of an 8 year old girl with a history of multiple fractures and bilateral dislocation of radial heads was received for consultation. CONCLUSIONS: Generalised osteoporosis with multiple fractures, periosteal thickening and bilateral dislocation of the radial heads are characteristic signs of osteogenesis imperfecta Type V. The Nosology and Classification of Genetic Skeletal Disorders 2006 Revision classified Osteogenesis Imperfecta into 8 major types. Type V is recognizable on the basis of skeletal survey alone.
RESUMEN
BACKGROUND: Pyle disease is a rare autosomal recessive bone dysplasia characterized by the broadening of metaphyses with generalized cortical thinning. Homozygous truncating mutations in secreted frizzled-related protein 4 (SFRP4) were, to date, the only known variants causative for this type of skeletal disorder. SFRP4 controls cortical and trabecular bone remodeling by differential regulation of the canonical and non-canonical WNT signaling in both bone compartments. Loss-of-function mutations in the SFRP4 gene lead to the protein deficiency causing skeletal phenotype typical for Pyle disease. RESULTS: Herein, we report on the first SFRP4 missense mutations that occurred in compound heterozygosity in two siblings affected by Pyle disease, and which we have identified using a whole-genome sequencing approach followed by a comprehensive in silico pathogenicity assessment. The variants we have found were extremely rare and evaluated to be disease-causing by several online available tools and software. CONCLUSION: With this paper, we have shown that Pyle disease may be related not only to SFRP4 truncating mutations but also to other loss-of-function alterations that possibly impair the protein capacity to bind WNT ligands. As we have expanded here, the range of deleterious variants underlying Pyle disease, we contribute to the knowledge on the pathogenesis of this rare skeletal disorder.
RESUMEN
We report on two siblings with a severe neonatal form of spondylometaphyseal dysplasia (SMD). Similar cases have been reported in four publications. Analysis of pedigree data from the original and present families suggests an autosomal recessive mode of inheritance, although parental gonadal mosaicism is also possible. The similarities in the phenotype between our patients and spondyloepimetaphyseal dysplasia congenita (SEMDC) and spondyloepimetaphyseal dysplasia Strudwick (SEMDS) type, indicated that these patients could have a defect in the COL2A1 gene. Molecular analysis of genomic DNA of these patients excluded this gene. Another potential candidate gene PTHR1, was also analyzed in the selected regions and no mutation was found. This gene is probably causative in the Jansen type of SMD, which shares some phenotypic features with the siblings whom we documented. Our results indicate that a new candidate gene for the reported form of SMD should be sought.
Asunto(s)
Osteocondrodisplasias/diagnóstico , Hermanos , Niño , Colágeno Tipo II/genética , Análisis Mutacional de ADN , Diagnóstico Diferencial , Femenino , Humanos , Recién Nacido , Enfermedades del Recién Nacido/diagnóstico , Enfermedades del Recién Nacido/genética , Masculino , Osteocondrodisplasias/congénito , Osteocondrodisplasias/genética , Receptor de Hormona Paratiroídea Tipo 1/genética , Índice de Severidad de la EnfermedadRESUMEN
In this paper, we report a boy with remarkable phenotype and noteworthy radiographic abnormalities. He presented with distinctive facies, mesomelic shortening and asymmetry of the extremities, symmetrical ulnar and fibular ray absence in the hands and feet, with unique hypoplastic/dysplastic radiographic abnormalities. His mental development was normal. We believe that he represents a previously unreported form of the postaxial acrofacial dysostosis syndrome.
Asunto(s)
Anomalías Múltiples/diagnóstico por imagen , Disostosis Craneofacial/diagnóstico por imagen , Deformidades Congénitas de las Extremidades/diagnóstico por imagen , Adolescente , Oído Externo/anomalías , Humanos , Masculino , Disostosis Mandibulofacial/diagnóstico por imagen , Micrognatismo/diagnóstico por imagen , Fenotipo , Radiografía , SíndromeRESUMEN
Czech dysplasia metatarsal type is an autosomal-dominant disorder characterized by an early-onset, progressive spondyloarthropathy with normal stature. Shortness of third and/or fourth toes is a frequently observed clinical feature. Similarities between individuals with this dysplasia and patients with an R275C mutation in the COL2A1 gene, prompted us to analyze the COL2A1 gene in the original families reported with Czech dysplasia. Targeted sequencing of exon 13 of the COL2A1 gene was performed, followed by sequencing of the remaining exons in case the R275C mutation was not identified. We identified the R275C substitution in two of the original patients reported with Czech dysplasia and three additional patients. All affected individuals had a similar phenotype characterized by normal height, spondyloarthropathy, short postaxial toes and absence of ocular and orofacial anomalies. The R275C mutation was excluded in a third patient reported with Czech dysplasia. However, the identification of the Y1391C mutation in this patient with disproportionate short stature made the diagnosis of spondyloperipheral dysplasia (SPD) more probable. The Y1391C mutation is located in the C-propeptide of the procollagen chain and has been reported before in a patient with the Torrance type of lethal platyspondylic skeletal dysplasia (PLSD-T). Our observation of the same Y1391C mutation in an additional unrelated patient with SPD further supports the evidence that PLSD-T and SPD represent a phenotypic continuum. The R275C mutation in the COL2A1 gene causes a specific type II collagen disorder that was recently delineated as Czech dysplasia.
Asunto(s)
Colágeno Tipo II/metabolismo , Deformidades Congénitas del Pie/patología , Proteínas de Unión al Calcio/química , Niño , Colágeno Tipo II/química , Colágeno Tipo II/genética , República Checa , Deformidades Congénitas del Pie/diagnóstico por imagen , Humanos , Rodilla/diagnóstico por imagen , Huesos Metatarsianos/diagnóstico por imagen , Huesos Metatarsianos/patología , Mutación/genética , Osteocondrodisplasias/diagnóstico por imagen , Osteocondrodisplasias/patología , RadiografíaRESUMEN
Spondylometaphyseal dysplasia Kozlowski type (SMDK) is a monogenic disorder within the TRPV4 dysplasia spectrum and has characteristic spinal and metaphyseal changes. We report skeletal MR imaging in a two-year-old patient who manifested typical clinical and radiographic features of SMDK. The diagnosis was confirmed by molecular analysis which revealed a mutation NM_021625.4:c.1781G > A - p.(Arg594His) in exon 11 of the TRPV4 gene. We have documented abnormalities in endochondral formation of the long and short tubular bones as well as round bones of the wrists and feet. The vertebral bodies had increased thickness of hyaline cartilage which enveloped ossification centers. The vertebrae and discs also had abnormalities in size, shape and structure. These anomalies were most likely the consequence of notochordal remnants presence within the intervertebral discs and in the vertebral bodies. The advantages of MR imaging in bone dysplasias caused by TRPV4 mutations are emphasized in this article.
Asunto(s)
Anomalías Múltiples/genética , Artrogriposis/genética , Anomalías Craneofaciales/genética , Mutación Missense , Osificación Heterotópica/diagnóstico por imagen , Osteocondrodisplasias/genética , Canales Catiónicos TRPV/genética , Anomalías Múltiples/diagnóstico , Artrogriposis/diagnóstico , Anomalías Craneofaciales/diagnóstico , Humanos , Cartílago Hialino/diagnóstico por imagen , Lactante , Disco Intervertebral/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Notocorda/diagnóstico por imagen , Osteocondrodisplasias/diagnóstico , Columna Vertebral/diagnóstico por imagenRESUMEN
BACKGROUND: Invasive CMV disease in transplanted organ recipients is a life threatening condition. CMV infection is also known risk factor for acute rejection and chronic allograft nephropathy. The risk of CMV infection in pediatric population is high, especially in terms of primary infection. It can be significantly reduced under long term (3 months) prophylaxis with ganciclovir (GCV), available exclusively as parenteral drug. Since recently oral tablet pro-drug valganciclovir (VCV, Valcyte, Roche) is given in adult patients. This drug has proved similar efficacy and good bioavailability (roughly 70%), however there is no registered liquid form which can be precisely and safety administered in small children. MATERIAL AND METHOD: 10 children after kidney transplantation, aged 2-9.5 year (mean 5.1; SD +/- 2.3), body weight 8.5-19.5 kg (mean 14.6; SD +/- 3.5), with good graft function (serum creatinine 0.3-0.8 mg/dl) were given VCV oral suspension prepared in hospital pharmacy, using Valcyte tablets and commercially available vehicle (Paddock Laboratories, Inc) (60 mg/ml), 7.5 mg/kg b.w., 2-3 x/day. Through level (CO) of GCV in blood was measured in all patient, in 4 patient drug kinetics (4 measurements) was also analyzed preceded with evaluation of GCV elimination after intravenous infusion of GCV. RESULTS: There was no episode of drug toxicity nor drug withdrawal from other reason. CO (mean = 0.74 microg/ml; max. 1.15; min. 0.38; SD +/- 0.25) was close to predefined values (0.4-1.0 microg/ml). Concentration profile of GCV (Cmax 1.0-1.5 h post dose) was similar to profile observed in adult patient treated with VCG tablets. CONCLUSION: Treatment with VCV suspension provides precise dosage and seems to be safe in patient with low body weight. It enables ambulatory prophylaxis and treatment of CMV infection.
Asunto(s)
Infecciones por Citomegalovirus/prevención & control , Ganciclovir/análogos & derivados , Profármacos/administración & dosificación , Profármacos/farmacocinética , Tolerancia al Trasplante , Administración Oral , Disponibilidad Biológica , Niño , Preescolar , Infecciones por Citomegalovirus/inmunología , Ganciclovir/administración & dosificación , Ganciclovir/farmacocinética , Humanos , Huésped Inmunocomprometido/inmunología , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/inmunología , Suspensiones , ValganciclovirRESUMEN
We describe two new cases of a rare form of lethal chondrodysplasia punctata (so-called X-linked dominant, non-rhizomelic form), a condition characterized by widespread multicentric stippled calcifications of the cartilaginous parts of the long bones, spine, ribs and flat bones. The mother of one of the patients had bone dysplasia consistent with the X-linked dominant form of chondrodysplasia punctata. We suggest that a skeletal survey, including lateral view of the spine, together with biochemical studies of peroxisomal status are indicated in all newborns with severe, unusual forms of chondrodysplasia punctata. In this way, accurate categorization of the lethal, non-rhizomelic types of this condition will be facilitated.
Asunto(s)
Condrodisplasia Punctata Rizomélica/patología , Adulto , Condrodisplasia Punctata Rizomélica/diagnóstico por imagen , Condrodisplasia Punctata Rizomélica/genética , Resultado Fatal , Femenino , Ligamiento Genético , Humanos , Recién Nacido , Radiografía , Cromosoma XRESUMEN
Radiograms of 173 children with unilateral Perthes disease were reviewed with particular reference to the presence of flattening and irregularity of the 'unaffected' epiphyses. The slope and shape of the growth plate were also evaluated. About 35% of children with Perthes disease showed changes of the unaffected proximal femur in the first radiograms of the hip joints. These consisted of small epiphysis, flattening of the epiphysis, contour irregularities (20%), and changes in the growth plate (15%). The radiographic abnormalities were not accompanied by any clinical symptoms of the asymptomatic hip joint and they receded with age during treatment.
Asunto(s)
Epífisis/diagnóstico por imagen , Fémur/diagnóstico por imagen , Placa de Crecimiento/diagnóstico por imagen , Articulación de la Cadera/diagnóstico por imagen , Enfermedad de Legg-Calve-Perthes/diagnóstico por imagen , Factores de Edad , Estudios de Casos y Controles , Niño , Preescolar , Descalcificación Patológica/diagnóstico por imagen , Epífisis/patología , Femenino , Fémur/patología , Placa de Crecimiento/patología , Articulación de la Cadera/patología , Humanos , Masculino , RadiografíaRESUMEN
We have documented the clinical and radiological features of a girl with a severe form of spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic or Hall type, which is associated with marked articular hypermobility. This condition is to be differentiated clinically from generalized hypermobility syndromes specifically Ehlers-Danlos syndrome and Larsen syndrome. The radiographic differential diagnosis is with the group of spondyloepimetaphyseal dysplasias specifically spondyloepimetaphyseal dysplasia with joint laxity and sponastrime dysplasia.